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Breast Cancer Study Informs Affibody, GE HealthCare's Development Path for HER2 Radiopharmaceutical

PET scanner

NEW YORK – Affibody and GE HealthCare's development plans for 68Ga-ABY-025 are starting to take shape after the diagnostic radiopharmaceutical showed it could predict which breast cancer patients benefit from HER2-targeted treatment in a Phase II trial.

In a study published last month in the Journal of Nuclear Medicine, a group of Swedish researchers showed that especially among patients with metastatic breast cancer, uptake of the gallium 68-labeled PET imaging agent 68Ga-ABY-025 correlated with metabolic response to HER2-targeted treatment, such as Genentech's Herceptin (trastuzumab), Perjeta (pertuzumab), or Kadcyla (trastuzumab emtansine).

"When it comes to predicting treatment outcomes in recurrent metastatic breast cancer, the radiopharmaceutical approach showed an advantage over traditional methods like IHC," said first author Ali Alhuseinalkhudhur, a Ph.D. candidate in Uppsala University's Department of Immunology, Genetics, and Pathology.

Immunohistochemistry (IHC) testing of a biopsied tumor sample, with or without fluorescence in situ hybridization, has long been the go-to method for determining patients' HER2 expression and targeted treatment eligibility. But biopsies aren't always feasible, and tumor cells at different metastatic sites can vary in terms of HER2 expression. This heterogenous HER2 expression can also change as patients receive treatment, and as they get sicker, repeat biopsies can become more invasive and impractical.

For this reason, Alhuseinalkhudhur and colleagues wanted to study the potential for a less-invasive, whole-body imaging approach as a way to visualize the HER2 expression levels of all of a patient's cancer cells at once.

The imaging peptide ABY-025 — labeled with the radioisotope gallium 68 to allow HER2-expressing cells to show up on a PET scan — is jointly developed by the Swedish company Affibody and GE HealthCare. The new study, Alhuseinalkhudhur noted, was an academic project sponsored by grants from the Swedish Breast Cancer Association, the Swedish Cancer Foundation, the Percy Falk Foundation, and Roche Sweden, which owns the HER2-targeted drugs that trial participants received.

In the study, which was part of a larger Phase II/III diagnostic trial, researchers evaluated 40 patients with confirmed HER2-positive breast cancer, 19 with newly diagnosed primary breast cancer, and 21 with metastatic breast cancer who had received a median three lines of treatment.

The newly diagnosed patients had stage II or stage III disease and were scheduled to receive neoadjuvant treatment. Patients with metastatic breast cancer were scheduled to receive HER2-targeted therapy plus chemotherapy.

Prior to treatment, patients underwent a needle biopsy and a PET/CT scan after being injected with the gallium-labeled radiopharmaceutical. At baseline and post-treatment, researchers used fluorine 18-labeled PET scans, a routine method for monitoring metabolic treatment responses across various cancer types, to gauge patients' responses. The researchers referred to this measurement as the change in tumor lesion glycolysis.

After patients underwent baseline testing, researchers compared the standard uptake variant, or SUV, of the gallium-labeled ABY-025 PET scans to determine HER2 expression levels. They also looked at these SUVs alongside the change in tumor lesion glycolysis following two rounds of treatment.

Here, they noticed that when a maximum SUV, or SUVmax, of 6.0 for the gallium-labeled radiopharmaceutical uptake was used as a cutoff to separate HER2-positive tumors from HER2-negtive tumors, 12 out of 40 patients had a different HER2 status by PET imaging than by conventional IHC testing.

This was surprising for Alhuseinalkhudhur and his team, who had gone into the study expecting that the two diagnostic methods would produce the same HER2 status in patients.

Discordance, treatment implications

The Phase II trial failed to meet its primary endpoint of showing concordance in HER2 positivity between 68Ga-ABY-025 imaging and IHC testing. Instead of interpreting this discordance as a sign that 68Ga-ABY-025 imaging isn't as reliable for determining HER2 status as expected, Alhuseinalkhudhur and colleagues realized their findings suggested instead that there were cases where IHC-based HER2 expression might not predict response to HER2-targeted treatment.

These were tumors that expressed HER2 as gauged by IHC but, for whatever reason, did not take up the HER2-targeted radiopharmaceutical. The same mechanism preventing the tumor from taking up 68Ga-ABY-025 could be the reason these tumors also saw a lower metabolic response to HER2-targeted treatment, the researchers suspected.

They found that the 68Ga-ABY-025 cutoff of SUVmax 6.0 predicted patients' changes in tumor lesion glycolysis and that the gallium-labeled radiopharmaceutical was a better predictor of treatment response than IHC, particularly in the metastatic breast cancer cohort.

"This shows that HER2 receptors are not necessarily always accessible to trastuzumab even if IHC showed positive overexpression," Alhuseinalkhudhur said, explaining that one reason for this could be that the HER2-targeting antibodies used for ex vivo diagnosis target the intracellular portion of the HER2 receptor, while the 68Ga-ABY-025 and therapeutic agents target the extracellular domain.

"The results showed that immunohistochemistry staining did not always reflect the biologic availability of the receptors," Alhuseinalkhudhur and coauthors further noted in their Journal of Nuclear Medicine paper. "A HER2-positive biopsy sample with low 68Ga-ABY-025 uptake could be explained by obstacles with tracer binding, potentially also affecting the access of trastuzumab to the receptor, and a positive biopsy with negative PET was associated with poor outcome in the metastatic breast cancer group."

Importantly, all of the treatment-naïve patients responded to treatment to a certain extent, regardless of 68Ga-ABY-025 uptake. Based on this, Alhuseinalkhudhur emphasized that the implications for the study's findings are most relevant to previously treated metastatic breast cancer patients.

Looking ahead, Alhuseinalkhudhur said 68Ga-ABY-025 imaging could be most useful in situations where biopsies are risky or inaccessible, or where additional information could help personalize treatment. For instance, it could be valuable to see full-body HER2 expression on a 68Ga-ABY-025 PET scan before deciding on the best treatment path, especially in instances where HER2 expression is heterogenous, or when oncologists suspect a patient's tumor has developed resistance mechanisms to HER2-targeted treatment.

In this study, patients who had experienced multiple recurrences following many lines of treatment were those least likely to respond to Herceptin, he pointed out. This was true even for some tumors with high 68Ga-ABY-025 uptake. For these patients, the results could suggest their cancers developed a new way to resist treatment while maintaining HER2 expression, he noted. This could have implications for identifying the next treatment strategy, for example, a HER2-targeting radiopharmaceutical that attaches a therapeutic isotope to a molecule like ABY-025 rather than the diagnostic isotope gallium, but Alhuseinalkhudhur emphasized that such a treatment would be the product of significantly more research.

The notion of using a HER2-targeting radiopharmaceutical to visualize HER2-targeting lesions with gallium 68, then swapping that gallium 68 out for a therapeutic isotope to treat the cancers based on their PET imaging results, is still very new. There are some groups out there looking into ABY-025 analogs labeled with lutetium-177 combined with Herceptin, he said, but those studies are still in the preclinical stages. There's also a concern about toxicity, Alhuseinalkhudhur added, since ABY-025 is known to have high kidney uptake.

Next steps, future research

On the whole, Alhuseinalkhudhur suspects it's unlikely that diagnostic radiopharmaceuticals would fully replace biopsy-based IHC testing to personalize HER2-targeted therapy. "Biopsy results are still essential, as they provide valuable information about other targetable biological markers, such as estrogen receptors as well as other prognostic and predictive characteristics," he said.

He added that it could be valuable to see wider multicenter studies interrogating the use of HER2-targeting radiopharmaceuticals for predicting treatment outcomes and guiding personalized therapies.

Alhuseinalkhudhur's own group, meanwhile, had to abort plans for a Phase III trial because this Phase II study did not meet its prespecified primary endpoint of showing that patients' HER2 status correlated between PET imaging with 68Ga-ABY-025 and IHC testing. Alhuseinalkhudhur didn't see this as a setback for HER2-targeted PET imaging so much as a sign that there are better endpoints to study in the HER2-targeted radiopharmaceutical space than IHC concordance.

"The intention now is to find partners and funding to start a new trial with the hypothesis that PET imaging can predict outcomes and alter therapy [decisions]," he said. "We think further clinical trials should have more clinically oriented endpoints."

Affibody also echoed this view from the commercial standpoint.

"It is a paradox," Affibody CSO Fredrik Frejd wrote via email. "Immunohistochemistry from biopsies has until now been seen as the best tool to predict response, but the reason our study did not meet the endpoint of correlation with IHC is that HER2-PET imaging predicted patients' responses to HER2 therapy much better than standard IHC."

Affibody is now gearing up to delve deeper into the question of HER2 heterogeneity in the wake of this study and a follow-on study with the Karolinska Institute assessing if conventional IHC does a particularly poor job describing HER2 expression status in HER2-low tumors.

"The ambition is to make this tracer available to patients in the near future," Frejd said.